New Drug Screening Technique Developed in Zebrafish Embryos

Process could lead to new treatments for diabetes and other diseases.

Finding the right drugs to treat diseases is oftentimes a daunting task for scientists, but what if it didn’t have to be?

Researchers at Johns Hopkins recently revealed in experiments with 500,000 genetically engineered zebrafish that they have potentially developed a better and more accurate way to screen for useful drugs. Investigators used the method to identify 24 drug candidates that increase the number of insulin-producing cells in the pancreas.

Researchers say this novel fish embryo technique could yield new treatments for diabetes and other diseases.

“More studies need to be done, but we think there’s potentially no limit on the diseases this screening technique could be applied to other than the human imagination,” said Jeffrey Mumm, PhD, associate professor of ophthalmology at the Johns Hopkins Wilmer Eye Institute and McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine.

The method was adapted from high throughput screening (HTS), an automated system developed in the 1980s that uses robotic equipment to “dose” cell or tissue samples with candidate drugs in wells of lab dishes known as microtiter plates. The plates are similar to miniature test tubes, enabling specially programmed computers to find chemical compounds that produce a desired effect, such as prompting cells to produce particular proteins or increase in number, positive findings known as hits.

Tens of thousands of samples can be processed daily thanks to the hundreds of wells contained in microtiter plates and the automated nature of the process. This increases the chance of finding a hit quickly.

However, the majority of hits found in the past from HTS techniques have not proven effective when tested in whole animals due to the fact that cells and tissues lack the complicated and dynamic biology of whole animals. Scientists turned to zebrafish embryos to solve this problem because zebrafish are transparent and share much of the genes with humans.

Researchers bred zebrafish with pancreatic beta cells that produce insulin glowing yellow and other pancreatic cells not responsible for producing insulin glowing red. The researchers placed the embryos in microtiter plate wells and tested thousands of compounds from a Johns Hopkins database of drugs, most of which were already approved for human use.

Scientists increased their chances of finding a hit rather than a false negative by screening each compound at 6 different concentrations. Computer programs automatically monitored the effects on the embryos by screening for differences in the amount of yellow glow, which signified an increase in beta cell number.

After taking into account over 500,000 zebrafish embryos, scientists identified 24 compounds that effectively increased beta cell number in these animals, according to Mumm. In addition to finding new drug candidates, the study also identified biological pathways not previously known to have an effect on beta cell production.

The researchers purport that if these newly identified drug candidates have the same effect in other lab models and, eventually, humans, they might someday be used directly to increase beta cell numbers in people who take them or for more effectively growing beta cells in the lab for transplant. Until then, the new technique can be used to speed drug discovery for a variety of medical conditions including heart disease, diabetes and neurodegenerative conditions.